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Deuterated phenyl amino pyrimidine compound and pharmaceutical composition containing the same

a phenylaminopyrimidine and compound technology, applied in the field of new deuterated phenylaminopyrimidine compounds, can solve the problems of drug resistance problems, side effects, druggability problems, etc., and achieve the effect of improving pharmacodynamic properties

Active Publication Date: 2017-03-28
SUZHOU ZELGEN BIOPHARML
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0101]Compared to non-deuterated compounds known in the prior art, the compounds of the present invention possess a number of advantages. Main advantages of the present invention comprise:

Problems solved by technology

Although the targeted inhibition of different protein kinases is beneficial for the treatment of kinase-related diseases, the discovery of novel compounds which specifically inhibit certain protein kinases and have druggability such as excellent oral bioavailability is still found challenging.
In addition, there are some side effects and drug resistance problems with some of the protein kinase inhibitors currently available on market.

Method used

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  • Deuterated phenyl amino pyrimidine compound and pharmaceutical composition containing the same
  • Deuterated phenyl amino pyrimidine compound and pharmaceutical composition containing the same
  • Deuterated phenyl amino pyrimidine compound and pharmaceutical composition containing the same

Examples

Experimental program
Comparison scheme
Effect test

example 1

the preparation of N-(cyanomethyl)-4-(2-(4-(d8-morpholino)phenyl amino)pyrimidine-4-yl)benzamide (compound 9)

[0107]

1. The preparation of 4-(4-nitrophenyl) (d8-morpholine) (compound 3)

[0108]Compound 4-chloronitrobenzene (3.53 g, 22.4 mmol), d8-morpholine (2.35 g, 24.6 mmol) and potassium carbonate (6.07 g, 44 mmol) were added into a flask sequentially, and dimethylsulfoxide (40 mL) was added. After that, it was heated up to 100° C. and was stirred for 16 h. TLC analysis (ethyl acetate / petroleum ether=1 / 10) showed that the reaction has completed. Then it was cooled to room temperature, and the reaction was quenched by adding water (100 mL). It was extracted by dichloromethane (100 mL) for two times. The combined organic layer was washed with water and saturated brine, dried with anhydrous sodium sulfate, filtered and concentrated under vacuum by rotary evaporator to give the crude product. It was crystallized in the mixed solvent of ethyl acetate and n-hexane (1 / 5, v / v, 18 mL) to obta...

example 2

The preparation of N-(cyanomethyl)-4-(2-(4-(d8-morpholino)phenyl amino)pyrimidine-4-yl)benzamide (compound 9)

[0113]

1. The preparation of 4-(4-nitrophenyl) (d8-morpholine) (compound 3)

[0114]4-chloronitrobenzene (0.662 g, 4.17 mmol), d8-morpholine (0.400 g, 4.17 mmol, purchased from Cambridge Isotope Laboratories) and potassium carbonate (1.733 g, 12.54 mmol) were added to a flask sequencially. Dimethylsulfoxide (6 mL) was added, then heated to 100° C., and stirred for 20 hours. The reaction mixture was cooled to room temperature, then water (30 mL) was added to quench the reaction, and there was yellow solid precipitated. After stirred for 30 min, the mixture was filtered to obtain the crude product. The crude product was crystallized in the mixed solvent of ethyl acetate and petroleum ether (1 / 2.5, v / v, 14 mL) to obtain the yellow solid desired product (0.600 g, HPLC purity: 98.6%, yield 67%).

2. The preparation of 4-(d8-morpholino)phenylamine (compound 4)

[0115]4-(4-nitrophenyl) (d8-...

example 3

The preparation of N-(cyano(d2-methyl))-4-(2-(4-(d8-morpholino)phenylamino)pyrimidin-4-yl)benzamide (compound 13)

1. The preparation of 2-amino-2,2-d2-acetonitrile hydrochloride (compound 12)

[0120]

[0121]Sodium cyanide (1.59 g, 32.46 mmol) and ammonia (6.80 g, 99.87 mmol) was added to the flask under ice bath, the inner temperature was controlled under 5° C., and ammonium chloride (2.27 g, 42.25 mmol) was added. After 10 min of stirring, deuterated formaldehyde (1.00 g, 31.21 mmol) was slowly added dropwise in 10 mins, and the inner temperature was controlled to be 16-20° C. After stirred under heat-preservation for 3 h, dichloromethane (100 ml) was added and stirred for 45 min, and liquid separated to obtain organic phase. The aqueous phase was extracted twice with dichloromethane (100 ml×2), the combined organic phase was dried over anhydrous sodium sulfate, and filtered. A solution of hydrogen chloride in isopropanol (15 mL) was added to the filtrate under ice bath, and was stirred...

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Abstract

The present invention relates to a deuterated phenyl amino pyrimidine compound and pharmaceutical composition containing the same. Specifically provided are a deuterated phenyl amino pyrimidine compound as represented by formula (I), and pharmaceutical composition containing the compound, or polymorph, pharmaceutically acceptable salt, hydrate or solvate thereof. The compound of the present invention can treat and / or prevent JAK kinase-related diseases, such as bone marrow proliferative disease, cancer, immunologic diseases and the like.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application is a Section 371 of International Application No. PCT / CN2014 / 071710, filed Jan. 28, 2014, which was published in the Chinese language on Jul. 31, 2014, under International Publication No. WO 2014 / 114274 A1, and the disclosure of which is incorporated herein by referenceTECHNICAL FIELD[0002]The present invention relates to the field of pharmaceutical. Specifically, the present invention relates to a new deuterated phenylamino pyrimidine compound, or the pharmaceutical compositions which comprises said compound.BACKGROUND OF THE INVENTION[0003]JAK (Janus kinase) is a type of non-receptor tyrosine kinase family, in which there are 4 members found, which are JAK1, JAK2, JAK3 and TYK1, respectively. They do not comprise SH2 or SH3 in their structure, and there are two connected kinase areas in their C-terminal. The substrate of JAK is STAT, i.e., signaling transducers and activators of transcription. STAT is dimerizeted after b...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/5377C07D413/12C07D239/42A61K45/06C07B59/00
CPCC07D239/42A61K31/5377A61K45/06C07B59/002C07D413/12A61P11/00A61P11/02A61P11/06A61P19/02A61P19/06A61P29/00A61P3/00A61P31/12A61P35/00A61P35/02A61P37/02A61P37/06A61P43/00A61P7/00A61P9/00
Inventor LV, BINHUASHENG, ZELINCAO, BENWEN
Owner SUZHOU ZELGEN BIOPHARML
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